T regulatory lymphocytes (Treg) maintain immune tolerance by suppressing both innate and adaptive immune cells. Tregs are atheroprotective, yet Treg phenotypes and function are disturbed during atherosclerosis progression. High-density lipoproteins (HDL) are atheroprotective, in large part due to their function in reverse cholesterol transport. However, HDL also performs cholesterol-independent functions, including the transport of sphingosine-1-phosphate (S1P), an important lipid mediator of immunity. Apolipoprotein M, found on HDL, binds S1P to aid in delivery of S1P to cells in the vasculature, including cells involved in adaptive immunity. Based upon our work and that of others, S1P most likely acts to impart differential effects on cytokine production by dendritic cells and lymphocyte depending on the microenvironment. We hypothesize that a novel function of HDL in adaptive immunity is related to the ability of HDL to stabilize Treg homeostasis and suppressive activity in vivo during atherogenesis. We will test our hypotheses in 2 specific aims. Specific Aim 1 will test the hypothesis that HDL regulates Treg homeostasis in atherosclerosis through S1P action. Specific Aim 2 will identify mechanisms for how HDL-S1P impacts both cell-autonomous dendritic cell and Treg actions to preserve Treg function in atherosclerosis.